Citations

TPS4205 Background: Multiple lines of evidence support the use of platinum-based chemotherapy for patients with homologous recombination deficiency-associated pancreatic adenocarcinoma (HRD PDAC; 15-20%). However, the impact of the specific platinum agent used remains uncertain. Mechanistically, oxaliplatin and cisplatin act distinctly on cancer cells, reflected in disparate toxicity profiles and target disease indications; furthermore, preclinical studies have shown that BRCA2-deficient cell lines and mice demonstrate significantly greater sensitivity to cisplatin compared to oxaliplatin. While oxaliplatin, part of the FOLFIRINOX regimen, represents the most commonly used platinum analogue for PDAC, clinical data shows that cisplatin (in combination with gemcitabine) can produce robust response rates (~70%) specifically in patients with germline BRCA/PALB2-mutated metastatic PDAC. We therefore designed a randomized clinical trial (PLATINUM) through the Alliance for Clinical Trials in Oncology cooperative group to assess the optimal chemotherapy regimen in patients with HRD-associated metastatic PDAC following front-line FOLFIRINOX and to test the hypothesis that a platinum switch strategy will be beneficial. Methods: The study consists of a seamless phase II/III design, with the primary endpoint of the phase III component being overall survival. Eligible patients will have metastatic PDAC, a confirmed pathogenic BRCA1/2 or PALB2 mutation (somatic or germline), and demonstrated disease progression on front-line FOLFIRINOX, with or without subsequent PARP inhibitor maintenance. Patients will be randomized 1:1 to receive (1) the de facto standard of gemcitabine plus nab-paclitaxel; or (2) the experimental 3-drug combination of gemcitabine, nab-paclitaxel, and cisplatin (NABPLAGEM), which has been previously studied in non-biomarker-selected patients with advanced biliary tract cancer (SWOG1815) and metastatic PDAC. Both treatment arms will use a once every other week dosing schedule. A total of 100 patients will be enrolled, which provides 90% power to detect an effect size of hazard ratio 0.5 (median OS of 18 vs 9 months) at a one-sided alpha of 0.05. Reports containing efficacy, adverse events, and administrative information will be provided to the Alliance DSMB every 6 months. Planned correlatives include ctDNA analysis for BRCA reversion mutations in all patients, as well as whole genome and transcriptome sequencing in an optional biopsy cohort. This study was activated in December 2023. Clinical trial information: NCT06115499 .

Abstract Background Sinonasal malignancies with orbital invasion have dismal prognosis even when treated with orbital exenteration (OE). Sugawara et al. developed a surgical strategy called “extended‐OE (EOE),” showing encouraging outcomes. We hypothesized that a similar resection is achievable under endoscopic guidance through the exenterated orbit (endoscopic‐EOE). Methods The study was conducted in three institutions: University of Vienna; Mayo Clinic; University of Insubria; 48 orbital dissections were performed. A questionnaire was developed to evaluate feasibility and safety of each step, scoring from 1 to 10, (“impossible” to “easy,” and “high risk” to “low risk,” respectively), most likely complication(s) were hypothesized. Results The step‐by‐step technique is thoroughly described. The questionnaire was answered by 25 anterior skull base surgeons from six countries. Mean, median, range, and interquartile range of both feasibility and safety scores are reported. Conclusions Endoscopic‐EOE is a challenging but feasible procedure. Clinical validation is required to assess real‐life outcomes.

TPS2698 Background: Chimeric antigen receptor (CAR) T-cell therapies for treating solid tumors are challenging due to a lack of tumor-specific targets that discriminate cancer from normal cells. Previous studies using CEA T-cell receptors and T-cell engagers have resulted in dose-limiting, on-target, off-tumor toxicities (1,2). A2B530 is an autologous logic-gated, CEA-targeted Tmod CAR T-cell therapy that addresses the challenges of on-target, off-tumor toxicity by combining a CAR-activating receptor with a blocking receptor to discriminate tumor from normal cells (3). The activator recognizes CEA on the surface of both tumor and normal cells while specificity for tumor cells is provided by a blocker that binds HLA-A*02. In patients with both germline HLA-A*02 and tumor-associated HLA-A*02 LOH, the blocker prevents on-target, off-tumor toxicity on normal cells owing to retained HLA-A*02 expression (4). HLA-A*02 LOH can be detected using next-generation sequencing (Tempus AI, Inc.). With this definitive discriminator target, A2B530 can potentially provide a therapeutic window to treat patients with CEA-expressing solid tumors exhibiting HLA LOH. Methods: EVEREST-1 (NCT05736731) is a seamless, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B530 in adult patients. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH at any time in the course of their disease. BASECAMP-1–eligible patients undergo leukapheresis and, when clinically appropriate, their banked T cells are manufactured for the EVEREST-1 study. The key inclusion criteria include histologically confirmed recurrent unresectable, locally advanced, or metastatic cancers associated with CEA expression: non-small cell lung, colorectal, or pancreatic cancers. Patients should have received ≥1 line of prior therapy such as checkpoint inhibitor, molecular targeted, or chemotherapy. The primary objective of phase 1 is to evaluate the safety and tolerability of A2B530 and determine the recommended phase 2 dose (RP2D). The dose-escalation portion is based on the Bayesian optimal interval design. The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B530. Phase 2 will assess overall response rate per RECIST v1.1. As of January 29, 2024, 8 patients have been enrolled on EVEREST-1. A2B530 was successfully manufactured for all patients, and all patients have received A2B530 infusion, with the first patient dosed in May 2023. Dose escalation is ongoing. 1. Parkhurst, et al. Mol Ther. 2022. 2. Tabernero, et al. J Clin Oncol. 2017. 3. Hamburger, et al. Mol Immunol. 2020. 4. Sandberg, et al. Sci Transl Med. 2022. Clinical trial information: NCT05736731 .

Abstract Aims Diagnosing myocardial infarction (MI) in patients with chronic kidney disease (CKD) is difficult as they often have increased high-sensitivity cardiac troponin T (hs-cTnT) concentrations. Methods and results Observational US cohort study of emergency department patients undergoing hs-cTnT measurement. Cases with ≥1 hs-cTnT increase > 99th percentile were adjudicated following the Fourth Universal Definition of MI. Diagnostic performance of baseline and serial 2 h hs-cTnT thresholds for ruling-in acute MI was compared between those without and with CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m2). The study cohort included 1992 patients, amongst whom 501 (25%) had CKD. There were 75 (15%) and 350 (70%) patients with CKD and 80 (5%) and 351 (24%) without CKD who had acute MI and myocardial injury. In CKD patients with baseline hs-cTnT thresholds of ≥52, >100, >200, or >300 ng/L, positive predictive values (PPVs) for MI were 36% (95% CI 28–45), 53% (95% CI 39–67), 73% (95% CI 50–89), and 80% (95% CI 44–98), and in those without CKD, 61% (95% CI 47–73), 69% (95% CI 49–85), 59% (95% CI 33–82), and 54% (95% CI 25–81). In CKD patients with a 2 h hs-cTnT delta of ≥10, >20, or >30 ng/L, PPVs were 66% (95% CI 51–79), 86% (95% CI 68–96), and 88% (95% CI 68–97), and in those without CKD, 64% (95% CI 50–76), 73% (95% CI 57–86), and 75% (95% CI 58–88). Conclusion Diagnostic performance of standard baseline and serial 2 h hs-cTnT thresholds to rule-in MI is suboptimal in CKD patients. It significantly improves when using higher baseline thresholds and delta values.

7012 Background: DLBCL with expression of MYC and BCL2 (double expressor lymphoma, DEL), has an adverse prognosis. Venetoclax, an inhibitor of BCL2, was previously studied in combination with R-CHOP. A051701 is a phase II/III randomized trial of chemoimmunotherapy +/- venetoclax in DEL and double hit lymphoma cohorts. Here we report initial phase II results from the DEL cohort. Methods: Patients (pts) age ≥ 18 years (y) with untreated DEL were randomized 1:1 to R-CHOP (Arm 1) or R-CHOP-venetoclax (Arm 2). DEL was defined as MYC expression ≥40% and BCL2 expression ≥50%, without double hit cytogenetics. Enrollment was based on local pathology results that were centrally confirmed. Venetoclax 800 mg was given orally days 4-8 of cycle 1 and days 1-5 of subsequent cycles for up to 6 cycles. All cycles were supported by GCSF or peg-GCSF. The primary endpoint was progression-free survival (PFS) with 84% power to detect a HR of 0.518 corresponding to 2y PFS rate of 65% in Arm 1 and 80% in Arm 2 (1-sided α=0.20). Results: 119 DEL pts were enrolled: 60 Arm 1; 59 Arm 2. Analyses were performed for the modified intent-to-treat population, defined as eligible pts with confirmed DEL histology (n=113; 56 Arm 1, 57 Arm 2). Median age was 64 y (range 22-85); baseline demographic factors were well balanced except for advanced stage (more common in Arm 1; (77% vs 60%, p=0.051). Most pts were non-germinal center B cell-like by immunohistochemistry (Arm 1 72%, Arm 2 58%), high-intermediate/high risk IPI (Arm 1 54%, Arm 2 51%) and ECOG performance status 0-1 (Arm 1 95%, Arm 2 86%). BCL2 rearrangements were detected in 25% and 33% of pts on Arm 1 and Arm 2, respectively. Most pts completed therapy per protocol (84% Arm 1, 75% Arm 2). Median follow up is 27 months (m). No difference in PFS was observed with 12-m PFS estimates of 77% in Arm 1, 76% in Arm 2 [HR = 0.98 (95% CI: 0.48 – 2.01), p=0.95]. The end of treatment (EOT) overall and complete response rates among patients with an EOT assessment were 87.5% and 70% in Arm 1, and 90% and 82% in Arm 2. Overall survival (OS) was not statistically significantly different with 12-mo OS estimates of 94% in Arm 1 and 79% in Arm 2 [HR = 1.27 (95% CI: 0.57 – 2.79), p=0.56]. Grade ≥3 adverse events (AEs) occurred more frequently in Arm 2 (42% vs 76%). The most commonly increased grade ≥3 AEs included neutropenia (20% vs 47%), anemia (4% vs 25.5%), thrombocytopenia (5.5% vs 24%), febrile neutropenia (7% vs 16%) and fatigue (0% vs 11%). No grade 5 AEs on treatment were reported on Arm 1, and 3 were reported on Arm 2 (lung infection and sudden death NOS, both possibly related; respiratory failure, unlikely related). Conclusions: Adding venetoclax to R-CHOP in DEL pts did not improve PFS and resulted in increased toxicity. The study did not meet its primary endpoint in phase II, and so did not proceed to phase III. Clinical trial information: NCT03984448 .

PURPOSE Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)–positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need. METHODS In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia. RESULTS After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively. CONCLUSION Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.

Abstract Rationale Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. Objectives By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. Methods We performed a genome-wide association study of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate genome-wide association study and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort (n = 1,278) and adults from the UKBiobank (n = 369,157). Measurements and Main Results CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating HHIP (hedgehog interacting protein), DSP, and NPNT as potential molecular targets based on colocalization of their expression. A higher dysanapsis genetic risk score was associated with obstructive spirometry among 5-year-old children and among adults in the fifth, sixth, and seventh decades of life. Conclusions CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development, and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endophenotype link between the genetic variations associated with lung function and COPD.

Abstract Introduction/Aims Point‐of‐care ultrasound of the diaphragm is highly sensitive and specific in the detection of neuromuscular diaphragmatic dysfunction. In some patients with neuromuscular diaphragmatic dysfunction, paradoxical thinning of the diaphragm during inspiration is observed on ultrasound; however, its frequency, electrodiagnostic associations, and prognostic significance remain uncertain. Methods Medical records of patients presenting to two electrodiagnostic laboratories (Mayo Clinic, Rochester, Minnesota and University of Alberta, Edmonton, Alberta) from January 1, 2022 to December 31, 2022, for evaluation of suspected neuromuscular respiratory failure, were reviewed. Results 214 patients were referred and 19 patients excluded due to incomplete information. Of 195 patients (384 hemidiaphragms), 104 had phrenic neuropathy, 12 had myopathy, and 79 had no evidence of neuromuscular disease affecting the diaphragm. Paradoxical thinning occurred in 31 (27%) patients with neuromuscular diaphragmatic dysfunction and was unilateral in 30, the majority (83%) having normal contralateral ultrasound. Phrenic nerve conduction studies and diaphragm electromyography results did not distinguish patients with paradoxical thinning versus without. Most patients (71%) with paradoxical thinning required non‐invasive ventilation (NIV), including 16 with unilateral paradoxical thinning. Paradoxical thinning and BMI ≥30 kg/m 2 were risk factors for requiring NIV in multivariable logistic regression analysis, with odds ratios of 2.887 (95% CI:1.166, 7.151) and 2.561 (95% CI: 1.186, 5.532), respectively. Discussion Paradoxical thinning of the diaphragm occurs in patients with prominent neuromuscular diaphragmatic dysfunction, most commonly from phrenic neuropathy, and is a significant risk factor for requiring NIV. Unilateral paradoxical thinning is sufficient for needing NIV. BMI ≥30 kg/m 2 additionally increases risk of requiring NIV in patients with neuromuscular diaphragmatic dysfunction.

Abstract The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 and single work groups in 2012 and 2018 to create recommendations for the diagnosis and characterization of Alzheimer's disease (AD). The present document updates the 2018 research framework in response to several recent developments. Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine (e.g., oncology), and is becoming a unifying concept common to all neurodegenerative diseases, not just AD. The present document is consistent with this principle. Our intent is to present objective criteria for diagnosis and staging AD, incorporating recent advances in biomarkers, to serve as a bridge between research and clinical care. These criteria are not intended to provide step‐by‐step clinical practice guidelines for clinical workflow or specific treatment protocols, but rather serve as general principles to inform diagnosis and staging of AD that reflect current science. Highlights We define Alzheimer's disease (AD) to be a biological process that begins with the appearance of AD neuropathologic change (ADNPC) while people are asymptomatic. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms. Early‐changing Core 1 biomarkers (amyloid positron emission tomography [PET], approved cerebrospinal fluid biomarkers, and accurate plasma biomarkers [especially phosphorylated tau 217]) map onto either the amyloid beta or AD tauopathy pathway; however, these reflect the presence of ADNPC more generally (i.e., both neuritic plaques and tangles). An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of AD and to inform clinical decision making throughout the disease continuum. Later‐changing Core 2 biomarkers (biofluid and tau PET) can provide prognostic information, and when abnormal, will increase confidence that AD is contributing to symptoms. An integrated biological and clinical staging scheme is described that accommodates the fact that common copathologies, cognitive reserve, and resistance may modify relationships between clinical and biological AD stages.